US5990109A - Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors - Google Patents
Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors Download PDFInfo
- Publication number
- US5990109A US5990109A US09/262,525 US26252599A US5990109A US 5990109 A US5990109 A US 5990109A US 26252599 A US26252599 A US 26252599A US 5990109 A US5990109 A US 5990109A
- Authority
- US
- United States
- Prior art keywords
- pyrido
- imidazo
- pyrazin
- chloro
- methylphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
Definitions
- the present invention relates to heterocyclo-substituted imidazopyrazines and salts thereof, to methods of using such compounds in treating protein tyrosine kinase-associated disorders such as immunologic disorders, and to pharmaceutical compositions containing such compounds.
- PTKs Protein tyrosine kinase
- PTKs comprise, inter alia, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet derived growth factor (PDGF), and kinases that play a role in angiogenesis (Tie-2 and KDR); and, in addition, non-receptor tyrosine kinases, including members of the Sky, JAK and Src (e.g., Src, Fyn, Lyn, Lck and Blk) families (see Bolen, J. B. Rowley, R. B., Spana, C., and Tsygankov, A.
- RPTKs receptor tyrosine kinases
- PTK inhibitors can thus impact a wide variety of oncologic and immunologic disorders. Such disorders may be ameliorated by selective inhibition of a certain receptor or non-receptor PTK, such as Lck, or due to the homology among PTK classes, by inhibition of more than one PTK by an inhibitor.
- a PTK of particular interest is Lck which is found in T cells where it is involved in phosphorylating key protein substrates. It is required for productive antigen receptor signaling and cell activation.
- TCR T cell receptor
- the kinase ZAP-70 is not activated, and Ca 2+ mobilization essential for T cell activation does not occur (see Weiss, A. and Littman, D. R. "Signal transduction by lymphocyte antigen receptors", Cell, 76, 263-274 (1994); Iwashima, M., Irving, B. A., van Oers, N. S. C., Chan, A.
- Inhibitors of Lck are thus useful in the treatment of T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
- T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus
- acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
- DTH delayed-type hypersensitivity
- the present invention provides heterocyclo-substituted imidazopyrazine compounds of the following formula I and salts thereof, for use as protein tyrosine kinase inhibitors: ##STR1## where Q, together with the atoms to which it is bonded, forms a 5-, 6- or 7-membered heterocyclic ring;
- each R 1 , and R 2 and R 3 are independently selected from:
- R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z 1 , Z 2 and one or more (preferably, one or two) groups Z 3 ;
- any two groups R 1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or
- any two groups R 1 may, together with the atoms to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;
- (1) are each independently hydrogen, R 6 , or --C(O)R 6 ; or
- (1) are each independently hydrogen or R 6 ;
- R 7 and R 8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or
- any two of R 9 , R 10 and R 11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;
- R 13 , R 14 and R 15 are each independently:
- Z 1 , Z 2 and Z 3 are each independently:
- Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z 1 , Z 2 and Z 3 ;
- any two of Z 1 , Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
- any two of Z 1 , Z 2 , and Z 3 may together be --O--(CH 2 ) q --O--;
- Z 4 and Z 5 are each independently:
- (1) are each independently hydrogen or Z 6 ;
- Z 7 and Z 8 , or Z 6 and Z 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or
- Z 7 or Z 8 together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; and
- Z 11 and Z 12 are each independently:
- alk or "alkyl” refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.
- lower alkyl refers to alkyl groups of 1 to 4 carbon atoms.
- alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
- alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. Where an alkynyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
- alkylene refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., --(CH 2 ) x -- wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
- alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups.
- alkenylene groups are --CH ⁇ CH--CH ⁇ CH--; --CH 2 --CH ⁇ CH--, --CH 2 --CH ⁇ CH--CH 2 --, --C(CH 3 ) 2 CH ⁇ CH-- and --CH(C 2 H 5 )--CH ⁇ CH--.
- alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups.
- exemplary alkynylene groups are --C.tbd.C--, --CH 2 --C.tbd.C--, --CH(CH 3 )--C.tbd.C-- and --C.tbd.C--CH(C 2 H 5 )CH 2 --.
- aromatic or aryl refer to phenyl, naphthyl and biphenyl.
- cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
- halogen and halo refer to fluorine, chlorine, bromine and iodine.
- unsaturated ring includes partially unsaturated and aromatic rings.
- heterocycle refers to fully saturated or unsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
- the heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.
- Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, diazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidin
- bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolin
- Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
- salts which are also within the scope of this invention.
- Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
- Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
- Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, aliginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, o
- Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
- organic bases for example, organic amines
- organic bases for example, organic amines
- benzathines dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines
- salts with amino acids such as arginine, lysine and the like.
- the basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
- lower alkyl halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
- dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
- Prodrugs and solvates of the compounds of the invention are also contemplated herein.
- the term "prodrug”, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof.
- Solvates of the compounds of formula I are preferably hydrates.
- compounds of the formula I, and salts thereof may exist in tautomeric form, for example, the form having the following structure, and salts thereof, where R 5 is hydrogen and Q, p, R 1 , R 2 , R 3 and R 4 are as defined above: ##STR2## All such tautomers are contemplated herein as part of the present invention.
- All stereoisomers of the present compounds are contemplated within the scope of this invention.
- Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
- the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
- Preferred compounds of the present invention are compounds of the formula I, and salts thereof, wherein Q, together with the atoms to which it is bonded, form pyridine, pyrimidine, pyrazole or imidazole and wherein one or more, and especially all, of p, R 1 , R 2 , R 3 , R 4 , and R 5 are selected from the following definitions:
- p 0, 1 or 2;
- each R 1 is independently selected from hydrogen; --OR 6 ; --Z 4 --NR 7 R 8 ; --Z 4 --N(R 12 )--Z 5 --R 6 ; alkoxy; nitro; halo; or alkyl, aryl or heterocyclo, each of which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;
- R 2 is selected from hydrogen, --Z 4 --N(R 9 )--Z 5 --NR 10 R 11 , or alkyl, where alkyl is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;
- R 3 is selected from hydrogen or alkyl
- R 4 is phenyl substituted with Z 1 , Z 2 and one or two groups Z 3 , where said Z 1 , Z 2 and Z 3 substituents are selected from hydrogen, halo, lower alkyl, lower alkoxy, --Z 4 --NZ 7 Z 8 , or heterocyclo; and
- R 5 is hydrogen
- the compounds of the formula I may be prepared by methods such as those illustrated in the following Schemes I to V. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. All documents cited are incorporated herein by reference in their entirety. Starting materials are commercially available or readily prepared by one of ordinary skill in the art.
- the method described herein may be carried out with starting materials and/or reagents in solution or alternatively, where appropriate, with one or more starting materials or reagents bound to a solid support (see (1) Thompson, L. A., Ellman, J. A., Chemical Reviews, 96, 555-600 (1996); (2) Terrett, N. K., Gardner, M., Gordon, D. W., Kobylecki, R. J., Steele, J., Tetrahedron, 51 8135-8173 (1995); (3) Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A., Gordon, E.
- an appropriately substituted nitro heterocyclo compound bearing leaving groups L 1 and L 2 (such as halo) 1 can be reacted with a substituted imidazole 2 in the presence of a base such as sodium, potassium, or cesium carbonate, or an amine base such as triethyl amine, diisopropylethyl amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (“DBU”), or the like, in an appropriate solvent to give the imidazole derivative 3 (Davey, et al., J. Med. Chem., 34, 2671 (1991)).
- L 2 may optionally be absent, where R 1 is hydrogen in the final compound I.
- L 2 group may be present on the ring Q where two or more groups R 1 are present in the final compound I.
- the reaction may also be carried out in the presence of a copper I salt such as cuprous chloride, cuprous bromide, or cuprous iodide (Sitkina, et al., Khim Geterotskil Soed in 143 (1966); Grimmett, et al., Aust. J. Chem., 32, 2203 (1979); Sugaya, et al., Synthesis, 73 (1994)).
- Preferred leaving groups in 1 are F and Cl in the absence of a copper I salt and Br and I in the presence of a copper I salt.
- the nitro group of 3 may then be reduced to provide the corresponding amine 4 by methods such as those known in the art (e.g., Hudlicky, "Reductions in Organic Chemistry", Wiley (1984)), for example, by catalytic hydrogenation, or by use of SnCl 2 , FeCl 3 , sodium dithionite, or the like.
- methods such as those known in the art (e.g., Hudlicky, "Reductions in Organic Chemistry", Wiley (1984)), for example, by catalytic hydrogenation, or by use of SnCl 2 , FeCl 3 , sodium dithionite, or the like.
- the amine 4 may be converted to the urea 7 by treatment with an isocyanate 5.
- amine 4 may first be reacted with an aryl chloroformate in the presence of an organic base such as diisopropylethyl amine to give an intermediate aryl carbamate. Treatment of this carbamate with the desired amine 6 provides the urea 7.
- Cyclization of the urea 7 to the desired imidazopyrazine 8 may be carried out using phosphorylchloride in the presence of pyridine via a chloroimidate intermediate (U.S. Pat. No. 4,191,766).
- Reagents other than POCl 3 which can also provide a reaction proceeding via the same chloroimidate intermediate (e.g., p-toluenesulfonyl chloride, PCl 5 , and the like) may be used.
- the L 2 group of 8 is replaced by R 1 to form a compound of the formula I by contact with a compound bearing R 1 in the presence of a base.
- 1,2- and 1,5-regioisomers may be formed, wherein the 2- or 5-position carbons of the imidazole ring of 7, respectively, become the bridgehead carbon of the fused imidazole ring of the final products.
- the 1,5-regioisomer provides the compound of the formula I
- the corresponding 1,2-regioisomer provides the compound having the following formula: ##STR4## It is preferred to obtain a compound of the formula I substantially free of its corresponding 1,2-regioisomer.
- the desired 1,5-regioisomer may be separated from the 1,2-isomer by methods such as fractional crystallization, or chromatography on silica gel or C-18.
- R 2 and R 3 are hydrogen in imidazole 2
- preferred R groups may be introduced at later points in the sequence by methods such as those known in the art. ##STR5##
- the aminoimidazole derivative 4 may be reacted with carbonyldiimidazole (CDI) or thiacarbonyldiimidazole, or alternatively phosgene or phosgene equivalents, to give the imidazopyrazine derivative 9(Davey, et al., J. Med. Chem., 34, 2671 (1991)).
- Imidazopyrazine derivative 9 may also exist as its tautomer 9a.
- Imidazopyrazine derivative 9 may be converted into its chloroimidate 10 in the presence of phosphorylchloride, or analogous reagents such as SOCl 2 , PCl 5 , PPh 3 /CCl 4 , or the like, and 10 reacted with the appropriate amine 11, in the presence of a base such as sodium, potassium, or cesium carbonate, or an amine base such as triethylamine, diisopropylethyl amine, DBU, or the like as required, to give compound 8 (Davey, et al., J. Med. Chem., 34, 2671 (1991)).
- Compound 8 can be converted to a compound of the formula I as described in Scheme I.
- compound 10 may be converted to thioether 12 by addition of a thiol to 10. Conversion to a compound of formula I may be carried out by addition of an amine 11 in the presence of a mercury II salt such as mercuric chloride or mercuric acetate (Foloppe, et al., Heterocycles, 36, 63 (1993)). ##STR6##
- a mercury II salt such as mercuric chloride or mercuric acetate
- an appropriately substituted amino heterocycle 13, where L 1 and L 2 are as defined above, may be converted to the corresponding amide 16 by either of two methods: 1) direct coupling with the N-protected imidazole carboxylic acid 14 using peptide coupling procedures such as standard methods known in the art (see, for example, Bodanszky, “Principles of peptide synthesis", Springer-Verlag (1984); Bodanszky and Bodansky, “The Practice of Peptide Chemistry", Springer-Verlag (1984)), followed by removal of the nitrogen protecting group P (see, for example, Greene, "Protective Groups in Organic Synthesis", Wiley (1991)); or 2) reaction of 13 with the dimer 15, the latter prepared by methods such as those known in the art (Kasina and Nematollahi, Synthesis, 162 (1975); Godefrol, et al., J.
- the dimer 15 may also be prepared by coupling the imidazole carboxylic acid: ##STR7## by contacting said acid with thionyl chloride or oxalyl chloride, preferably in the presence of dimethylformamide and heat.
- Amide 16 may then be converted to the imidazooxopyrazine 9 by methods analogous to those described for the conversion of 1 to 3 in Scheme I. Conversion of 9 to compound I may then be carried out as described in Scheme II. ##STR8##
- Compound 2 may be reacted with tosylmethylisocyanide ("TOSMIC") in the presence of a base such as sodium hydride, n-butyl lithium, lithium, sodium, potassium, or cesium carbonate, or the like to give the heterocyclo-substituted imidazole 25.
- TOSMIC tosylmethylisocyanide
- the compounds of the present invention inhibit protein tyrosine kinases, especially Src-family kinases such as Lck, Fyn, Lyn, Src, Yes, Hck, Fgr and Blk, and are thus useful in the treatment, including prevention and therapy, of protein tyrosine kinase-associated disorders such as immunologic disorders.
- protein tyrosine kinase-associated disorders are those disorders which result from aberrant tyrosine kinase activity, and/or which are alleviated by the inhibition of one or more of these enzymes.
- Lck inhibitors are of value in the treatment of a number of such disorders (for example, the treatment of autoimmune diseases), as Lck inhibition blocks T cell activation.
- T cell mediated diseases including inhibition of T cell activation and proliferation
- Compounds which selectively block T cell activation and proliferation are preferred.
- Compounds of the present invention which block the activation of endothelial cell PTK by oxidative stress, thereby limiting surface expression of adhesion molecules that induce neutrophil binding, and which inhibit PTK necessary for neutrophil activation are useful, for example, in the treatment of ischemia and reperfusion injury.
- the present invention thus provides methods for the treatment of protein tyrosine kinase-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor.
- Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods.
- such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
- transplant such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)
- protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes
- transplantation tolerance induction arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; chronic obstructive pulmonary disease (COPD), such as emphysema; inflammatory bowel disease, including ulcerative colitis and Chron's disease; lupus (systemic lupus erythematosis); graft vs.
- transplant such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)
- protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes
- transplantation tolerance induction arthritis (such as rhe
- T-cell mediated hypersensitivity diseases including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune Hypothyroidism, such as Graves' Disease; Addison's disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; cancers where Lck or other Src-family kinases such as Src are activated or overexpressed, such as colon carcinoma and thymoma, or cancers where Src-family kinase activity facilitates tumor growth or survival; glomerulonephritis, serum sickness; uticaria; allergic diseases such as respiratory
- Src-family kinases other than Lck are important in the Fc gamma receptor induced respiratory burst of neutrophils as well as the Fc gamma receptor responses of monocytes and macrophages.
- the compounds of the present invention inhibit the Fc gamma induced respiratory burst response in neutrophils, and also inhibit the Fc gamma dependent production of TNF alpha in the monocyte cell line THP-1 that does not express Lck.
- the ability to inhibit Fc gamma receptor dependent neutrophil, monocyte and macrophage responses results in additional anti-inflammatory activity for the present compounds beyond their effects on T cells. This activity is especially of value, for example, in the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease.
- the present compounds are of value for the treatment of autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses leading to kidney damage.
- the present compounds also inhibit production of TNF alpha induced by other means, such as, by lipopolysaccharide (LPS).
- LPS lipopolysaccharide
- the compounds are of value for the treatment of toxic shock, septic shock, or other diseases caused by LPS produced by bacterial infection.
- Src family kinases other than Lck are important in the Fc epsilon receptor induced degranulation of mast cells and basophils that plays an important role in asthma, allergic rhinitis, and other allergic disease.
- Fc epsilon receptors are stimulated by IgE-antigen complexes.
- the compounds of the present invention inhibit the Fc epsilon induced degranulation responses, including in the basophil cell line RBL that does not express Lck.
- the ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses results in additional anti-inflammatory activity for the present compounds beyond their effect on T cells.
- the present compounds are of value for the treatment of asthma, allergic rhinitis, and other instances of allergic disease.
- the combined activity of the present compounds towards monocytes, macrophages, T cells, etc. may be of value in the treatment of any of the aforementioned disorders.
- the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, lupus, graft v. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic disease such as allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis whether or not associated with PTK.
- the present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating a protein tyrosine kinase-associated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent.
- the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
- the compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
- suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non
- the present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
- the present compounds may also be administered liposomally.
- compositions for oral administration include suspension which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
- the present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
- compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
- fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins
- compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
- compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
- suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
- compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
- a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
- compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
- a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
- the effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.1 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
- Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to protein tyrosine kinase-associated disorders.
- the compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of protein tyrosine kinase-associated disorders such as PTK inhibitors other than those of the present invention, antiinflammatories, antiproliferatives, chemotherapeutic agents, and immunosuppressants.
- suitable therapeutic agents useful in the treatment of protein tyrosine kinase-associated disorders such as PTK inhibitors other than those of the present invention, antiinflammatories, antiproliferatives, chemotherapeutic agents, and immunosuppressants.
- cyclosporins e.g., cyclosporin A
- CTLA4-Ig antibodies such as anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CF40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolim
- the human T cell antigen gp39 is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity", EMBO J (England), 11(12), p 4313-4321 (December 1992); and Moreland, L. W. et al., "Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (P75)-Fc fusion protein, New England J. of Medicine, 337(3), p. 141-147(1997).
- test compound a compound as a PTK inhibitor.
- test compound a compound described in the following Examples have been tested in one or more of these assays, and have shown activity.
- the following assay has been carried out using the protein tyrosine kinases Lck, Fyn, Lyn, Hck, Fgr, Src, Blk and Yes.
- the protein tyrosine kinase of interest is incubated in kinase buffer (20 mM MOPS, pH7, 10 mM MgCl 2 ) in the presence of the test compound.
- the reaction is initiated by the addition of substrates to the final concentration of 1 ⁇ M ATP, 3.3 ⁇ Ci/ml [33P] gamma-ATP, and 0.1 mg/ml acid denatured enolase (prepared as described in Cooper, J. A., Esch, F. S., Taylor, S. S., and Hunter, T., "Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro", J. Biol.
- This assay is advantageous as it employs an exogenous substrate (enolase) for more accurate enzyme kinetics, and can be conducted in a 96-well format that is readily automated.
- Enolase exogenous substrate
- His-tagged protein tyrosine kinases (described below) offer much higher production yields and purity relative to GST-protein tyrosine kinase fusion protein.
- the protein tyrosine kinase may be obtained from commercial sources or by recombinant methods described herewith.
- human Lck was prepared as a His-tagged fusion protein using the Life Technologies (Gibco) baculovirus vector pFastBac Hta (commercially available) in insect cells.
- pFastBac Hta commercially available
- a cDNA encoding human Lck isolated by PCR (polymerase chain reaction) was inserted into the vector and the protein was expressed using the methods described by the manufacturer.
- the Lck was purified by affinity chromatography.
- For the production of Lck in insect cells using baculovirus see Spana, C., O'Rourke, E. C., Bolen, J.
- Jurkat T cells are incubated with the test compound and then stimulated by the addition of antibody to CD3 (monoclonal antibody G19-4).
- Cells are lysed after 4 minutes or at another desired time by the addition of a lysis buffer containing NP-40 detergent.
- Phosphorylation of proteins is detected by anti-phosphotyrosine immunoblotting.
- Detection of phosphorylation of specific proteins of interest such as ZAP-70 is detected by immunoprecipitation with anti-ZAP-70 antibody followed by anti-phosphorylation immunoblotting.
- Such procedures are described in Schieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., Bolen, J. B., Kanner, S.
- Lck inhibitors block calcium mobilization in T cells stimulated with anti-CD3 antibodies.
- Cells are loaded with the calcium indicator dye indo-1, treated with anti-CD3 antibody such as the monoclonal antibody G19-4, and calcium mobilization is measured using flow cytometry by recording changes in the blue/violet indo-1 ratio as described in Schieven, G. L., Mittler, R. S., Nadler, S. G., Kirihara, J. M., Bolen, J. B., Kanner, S. B., and Ledbetter, J. A., "ZAP-70 tyrosine kinase, CD45 and T cell receptor involvement in UV and H 2 O 2 induced T cell signal transduction", J. Biol. Chem., 269, 20718-20726 (1994), and the references incorporated therein.
- Lck inhibitors inhibit the proliferation of normal human peripheral blood T cells stimulated to grow with anti-CD3 plus anti-CD28 antibodies.
- a 96 well plate is coated with a monoclonal antibody to CD3 (such as G19-4), the antibody is allowed to bind, and then the plate is washed. The antibody bound to the plate serves to stimulate the cells.
- Normal human peripheral blood T cells are added to the wells along with test compound plus anti-CD28 antibody to provide co-stimulation. After a desired period of time (e.g., 3 days), the [3H]-thymidine is added to the cells, and after further incubation to allow incorporation of the label into newly synthesized DNA, the cells are harvested and counted in a scintillation counter to measure cell proliferation.
- HPLC 3.255 min (YMC ODS-A C18 S-5 column, 4.6 ⁇ 50 mm, 4 min gradient from 0 to 100% B with 2 min hold at 100% B.
- Solvent A 90%H 2 O-10%MeOH-0.2%H 3 PO 4 ;
- Solvent B 10%H 2 O-90%MeOH-0.2% H 3 PO 4 ).
- Example 2 The following compounds 2 to 6 (Examples 2 to 6) were prepared from 1C by a route analogous to that used for the preparation of 1D. These compounds have the structure shown below: ##STR14## where W 1 is defined in the following Table 1. The HPLC retention times of Table 1 were obtained by the method of Example 1. "X 1 " in Table 1 is not a substituent, but rather shows the point of attachment of W 1 to the remainder of the compound of formula I. Unfilled valences on nitrogen indicate the presence of a hydrogen.
- Compound 7B was prepared by an analogous method as that of 1B, except the reaction was at 130° C.
- Compound 7C was prepared by an analogous method as that of 1C.
- Compound 7D was prepared by an analogous method to that of 1D. HPLC ret. time: 4.066 min. (method of Example 1).
- Example 48 to 50 were prepared from 14 by methods analogous to that used for the preparation of 47. These compounds have the structure shown below: ##STR103## where R 1 and W 1 are defined in the following Table 3. The HPLC retention times of Table 3 were obtained by the method of Example 1. "X 1 " and “X 2 " in Table 3 are not substituents, but rather show the point of attachment of R 1 and W 1 , respectively, to the remainder of the compound of formula I. Unfilled valences on nitrogen indicate the presence of a hydrogen.
- the title compound 51G was prepared from 51F by a route analogous to that used for the preparation of 1D.
- HPLC ret. time 2.389 min. (YMC ODS-A C18 S-5column, 4.6 ⁇ 50 mm. 4 min gradient from 0 to 100% B with 2 min hold at 100% B.
- Solvent A 90%H 2 )--10%MeOH--0.2%H 3 PO 4 ;
- Solvent B 10%H 2 O--90%MeOH--0.2%H 3 PO 4 ).
- the title compound 52 was prepared from 51F by a route analogous to that used for the preparation of 1D. HPLC ret. time: 2.292 min. (method of Example 51).
- Compound 53A was prepared from 3,4-diaminopyridine by a route analogous to that used for the preparation of 51C.
- Compound 53B was prepared by a method analogous to that used for the preparation of 51D.
- Compound 53C was prepared by a method analogous to that used for the preparation of 51E.
- Compound 53D was prepared by a method analogous to that used for the preparation of 51F.
- the title compound 53E was prepared from 53D by a method analogous to that used for the preparation of 1D.
- the title compound 54 was prepared from 53D by a method analogous to that used for the preparation of 1D.
- the title compound 55 was prepared from 7D by a method analogous to that used for the preparation of 8. HPLC Retention time: 2.250 min. (method of Example 1).
- the title compound 58 was prepared from 7D by a method analogous to that used for the preparation of 57.
- Compound 59A was prepared from 4-amino-2-chloro-5-fluoropyrimidine by a route analogous to that used for the preparation of 1A.
- Compound 59B was prepared from 59A by a method analogous to that used for the preparation of 1B.
- Compound 59D was prepared from 59C by a method analogous to that used for the preparation of 1C.
- the title compound 59E was prepared from 59D by a method analogous to that used for the preparation of 1D. HPLC Retention time: 3.53 min. (method of Example 51).
- 5-Chloro-1-methyl-imidazole (4.0 g, 34.32 mmol) was dissolved in a mixture of 4.0 g of conc. nitric acid and 14 mL of water, and concentrated in vacuo to give a yellow slurry. To this mixture was added dropwise 12 g of conc. sulfuric acid and heated to 95° C. for 2 hours. Upon cooling, ice was added to the reaction mixture, which was then left standing 10 hours at 5° C. The white precipitation was collected by filtration, washed with water, recrystallized from ethanol and dried in vacuo to give compound 60A.
- the title compound 61 was prepared starting from 5-chloro-1,3-dimethyl-4-nitropyrazole by a route analogous to that used for the preparation of 60D. HPLC Retention time: 2.04 min. (method of Example 51).
- the title compound 62 was prepared from 7C by a route analogous to that used for the preparation of 8. HPLC Retention time: 2.243 min. (method of Example 1).
- the title compound 63 was prepared from 7C by a route analogous to that used for the preparation of 8. HPLC Retention time: 2.396 min. (method of Example 1).
- Compound 172C was prepared from 172B by an analogous method as that of 7A.
- Compound 172D was prepared from 172C by an analogous method as that of 7B, except that K 2 CO 3 was replaced with DBU, dimethylacetamide was replaced with DMF, and the mixture was heated at 150-160° C. for 1.0 hour.
- Compound 172E was prepared from 172D by an analogous method as that of 7C.
- Compound 172F was prepared from 172E by an analogous method as that of 7D.
- the title compound 172G was prepared from 172F by an analogous method as that 8. HPLC ret. time: 2.304 min (method of Example 1).
- Compound 173 was prepared from 172F by an analogous method as that of 8. HPLC ret. time: 2.404 min (method of Example 1).
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/262,525 US5990109A (en) | 1998-03-04 | 1999-03-04 | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7678998P | 1998-03-04 | 1998-03-04 | |
US09/262,525 US5990109A (en) | 1998-03-04 | 1999-03-04 | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
US5990109A true US5990109A (en) | 1999-11-23 |
Family
ID=22134195
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/262,525 Expired - Lifetime US5990109A (en) | 1998-03-04 | 1999-03-04 | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors |
Country Status (11)
Country | Link |
---|---|
US (1) | US5990109A (de) |
EP (1) | EP1066286B1 (de) |
JP (1) | JP2002505330A (de) |
AR (1) | AR018311A1 (de) |
AT (1) | ATE430149T1 (de) |
AU (1) | AU756838B2 (de) |
CA (1) | CA2322311C (de) |
DE (1) | DE69940808D1 (de) |
ES (1) | ES2324846T3 (de) |
WO (1) | WO1999045009A1 (de) |
ZA (1) | ZA991721B (de) |
Cited By (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010055593A1 (en) * | 2000-03-14 | 2001-12-27 | Joseph Sypek | Use of rapamycin and agents that inhibit B7 activity in immunomodulation |
WO2002047710A2 (en) * | 2000-12-11 | 2002-06-20 | Children's Medical Center Corporation | Use of inhibitors of lyn-associated signal transduction (last) in the treatment of prostate cancer |
WO2002063037A2 (en) * | 2001-02-02 | 2002-08-15 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Method for identifying functional nucleic acids |
WO2003097044A1 (en) * | 2002-05-16 | 2003-11-27 | Pharmacia Corporation | Methods using a combination of a 3-heteroaryl-2-indolinone and a cyclooxygenase-2 inhibitor for the treatment of neoplasia |
WO2004004644A2 (en) * | 2002-07-05 | 2004-01-15 | Beth Israel Deaconess Medical Center | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
US20040063765A1 (en) * | 2002-03-08 | 2004-04-01 | 4 Sc Ag | Modulation of pathogenicity |
US20040171587A1 (en) * | 2002-12-06 | 2004-09-02 | Borgens Richard B. | Pyridines for treating injured mammalian nerve tissue |
US20040180898A1 (en) * | 2003-03-03 | 2004-09-16 | Bang-Chi Chen | Processes for preparing imidazoquinoxalinones, heterocyclic-substituted imidazopyrazinones, imidazoquinoxalines and heterocyclic-substituted imidazopyrazines |
US20040235914A1 (en) * | 2002-03-08 | 2004-11-25 | 4 Sc Ag | Modulation of pathogenicity |
US20050008640A1 (en) * | 2003-04-23 | 2005-01-13 | Wendy Waegell | Method of treating transplant rejection |
US20050131018A1 (en) * | 2003-08-20 | 2005-06-16 | Axys Pharmaceuticals, Inc. | Acetylene derivatives as inhibitors of histone deacetylase |
US6960585B2 (en) | 2000-10-03 | 2005-11-01 | Bristol-Myers Squibb Company | Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and pharmaceutical compositions comprising same |
US20060079556A1 (en) * | 2004-10-12 | 2006-04-13 | Sher Philip M | N-sulfonylpiperidine cannabinoid receptor 1 antagonists |
US20060154955A1 (en) * | 2005-01-12 | 2006-07-13 | Chongqing Sun | Bicyclic heterocycles as cannabinoid receptor modulators |
US20060155126A1 (en) * | 2005-01-12 | 2006-07-13 | Chongqing Sun | Bicyclic heterocycles as cannabinoid receptor modulators |
US20060178386A1 (en) * | 2005-02-10 | 2006-08-10 | Saleem Ahmad | Dihydroquinazolinones as 5HT modulators |
US20060287323A1 (en) * | 2005-06-17 | 2006-12-21 | Ewing William R | Azabicyclic heterocycles as cannabinoid receptor modulators |
US20060287342A1 (en) * | 2005-06-17 | 2006-12-21 | Mikkilineni Amarendra B | Triazolopyrimidine heterocycles as cannabinoid receptor modulators |
US20060287324A1 (en) * | 2005-06-17 | 2006-12-21 | Chongqing Sun | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
US20060287341A1 (en) * | 2005-06-17 | 2006-12-21 | Gang Wu | Triazolopyrimidine cannabinoid receptor 1 antagonists |
US20070004772A1 (en) * | 2005-06-17 | 2007-01-04 | Chongqing Sun | Triazolopyridine cannabinoid receptor 1 antagonists |
US20070014832A1 (en) * | 1999-12-07 | 2007-01-18 | Rutgers, The State Univesity Of New Jersey | Therapeutic compositions and methods |
US20070027178A1 (en) * | 2005-07-28 | 2007-02-01 | Bristol-Myers Squibb Company | Substituted tetrahydro-1H-pyrido[4,3-b]indoles as serotonin receptors agonists and antagonists |
US20070049613A1 (en) * | 2005-08-24 | 2007-03-01 | Bristol-Myers Squibb Company | Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists |
US20070093534A1 (en) * | 2003-05-06 | 2007-04-26 | Aldo Ammendola | Modulation of Pathogenicity |
US7220859B2 (en) | 2005-01-12 | 2007-05-22 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
US20080200459A1 (en) * | 2005-01-18 | 2008-08-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline cannabinoid receptor modulators |
US20090312338A1 (en) * | 2008-06-10 | 2009-12-17 | Abbott Laboratories | Novel Tricyclic Compounds |
US20100137246A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136094A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100136096A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100135983A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100137247A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136097A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100136095A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100179158A1 (en) * | 2007-04-20 | 2010-07-15 | Hoffman Charles S | Inhibitors of cyclic amp phosphodiesterases |
EP2226322A1 (de) * | 2007-12-27 | 2010-09-08 | Daiichi Sankyo Company, Limited | Imidazol-carbonyl-verbindung |
US20100227853A1 (en) * | 2008-04-18 | 2010-09-09 | Trustees Of Boston College | Inhibitors of cyclic amp phosphodiesterases |
US20110059961A1 (en) * | 2009-09-08 | 2011-03-10 | Xiaojing Wang | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
US20110130429A1 (en) * | 2002-12-06 | 2011-06-02 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US20110171218A1 (en) * | 2009-12-02 | 2011-07-14 | Acceleron Pharma Inc. | Compositions and methods for increasing serum half-life |
US20110190489A1 (en) * | 2009-12-01 | 2011-08-04 | Abbott Laboratories | Novel Tricyclic Compounds |
US8013017B2 (en) | 2001-05-31 | 2011-09-06 | Upsher-Smith Laboratories, Inc. | Dermatological compositions and methods |
US8557818B2 (en) | 2006-12-14 | 2013-10-15 | Vertex Phamaceuticals Incorporated | Compounds useful as protein kinase inhibitors |
US20130344061A1 (en) * | 2012-06-25 | 2013-12-26 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors |
US8618106B2 (en) | 2008-06-23 | 2013-12-31 | Vertex Pharmaceuticals Incorporated | Protein kinase inhibitors |
US8883982B2 (en) | 2011-06-08 | 2014-11-11 | Acceleron Pharma, Inc. | Compositions and methods for increasing serum half-life |
US9206182B2 (en) | 2009-07-15 | 2015-12-08 | Intellikine Llc | Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof |
US9290497B2 (en) | 2011-01-10 | 2016-03-22 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
US9365575B2 (en) | 2012-05-21 | 2016-06-14 | Allergan, Inc. | Kinase inhibitors |
US9387250B2 (en) | 2013-03-15 | 2016-07-12 | Rutgers, The State University Of New Jersey | Therapeutic compositions for bone repair |
US9822131B2 (en) | 2008-01-04 | 2017-11-21 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9879019B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
USRE47221E1 (en) | 2009-12-01 | 2019-02-05 | Abbvie Inc. | Tricyclic compounds |
US20190047982A1 (en) * | 2016-02-11 | 2019-02-14 | Bayer Cropscience Aktiengesellschaft | Substituted 2-(het)arylimidazolylcarboxyamides as pesticides |
US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11110096B2 (en) | 2014-04-16 | 2021-09-07 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11147818B2 (en) | 2016-06-24 | 2021-10-19 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11993606B2 (en) | 2023-08-21 | 2024-05-28 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
Families Citing this family (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7354894B2 (en) | 1998-08-18 | 2008-04-08 | The Regents Of The University Of California | Preventing airway mucus production by administration of EGF-R antagonists |
PL200940B1 (pl) | 1998-08-18 | 2009-02-27 | Univ California | Zastosowanie antagonisty receptora naskórkowego czynnika wzrostowego (EGF-R) i postać farmaceutyczna do leczenia nadmiernego wydzielania śluzu dróg oddechowych |
US20040102455A1 (en) * | 2001-01-30 | 2004-05-27 | Burns Christopher John | Method of inhibiting kinases |
NZ544797A (en) | 2003-07-18 | 2011-04-29 | Amgen Fremont Inc | Specific antibodies that bind HGF and neutralise binding of HGF to met |
JP5089392B2 (ja) * | 2004-10-13 | 2012-12-05 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | キナーゼ阻害剤としての複素環式置換ビスアリール尿素誘導体 |
WO2006060318A2 (en) | 2004-11-30 | 2006-06-08 | Amgen Inc. | Quinolines and quinazoline analogs and their use as medicaments for treating cancer |
US20080108664A1 (en) | 2005-12-23 | 2008-05-08 | Liu Belle B | Solid-state form of AMG 706 and pharmaceutical compositions thereof |
EP1987023B1 (de) | 2006-02-10 | 2010-11-24 | Amgen, Inc | Hydratformen von amg706 |
TW200815436A (en) * | 2006-05-30 | 2008-04-01 | Elbion Ag | 4-amino-pyrido[3,2-e]pyrazines, their use as inhibitors of phosphodiesterase 10, and processes for preparing them |
PE20121506A1 (es) | 2006-07-14 | 2012-11-26 | Amgen Inc | Compuestos triazolopiridinas como inhibidores de c-met |
US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
WO2008079291A2 (en) | 2006-12-20 | 2008-07-03 | Amgen Inc. | Substituted heterocycles and methods of use |
ES2449482T3 (es) | 2007-01-09 | 2014-03-19 | Amgen Inc. | Derivados de bis-aril-amida útiles para el tratamiento de cáncer |
US8314087B2 (en) | 2007-02-16 | 2012-11-20 | Amgen Inc. | Nitrogen-containing heterocyclyl ketones and methods of use |
WO2009026303A1 (en) | 2007-08-21 | 2009-02-26 | Amgen Inc. | Human c-fms antigen binding proteins |
US20090143361A1 (en) * | 2007-11-30 | 2009-06-04 | Elbion Gmbh | Pyrido[3,2-E]Pyrazines, Process For Preparing The Same, And Their Use As Inhibitors Of Phosphodiesterase 10 |
WO2009070584A1 (en) | 2007-11-30 | 2009-06-04 | Wyeth | Aryl and heteroaryl fused imidazo[1,5-a]pyrazines as inhibitors of phosphodiesterase 10 |
US20090143392A1 (en) * | 2007-11-30 | 2009-06-04 | Elbion Gmbh | Methods of Treating Obesity and Metabolic Disorders |
US20100075973A1 (en) * | 2008-08-28 | 2010-03-25 | Takeda Pharmaceutical Company Limited | Polo-like kinase inhibitors |
US8361962B2 (en) * | 2009-07-27 | 2013-01-29 | Roche Palo Alto Llc | Tricyclic inhibitors of JAK |
BR112012005382A2 (pt) | 2009-09-10 | 2016-03-29 | Hoffmann La Roche | inibidores de jak |
BR112012006176A2 (pt) | 2009-09-21 | 2015-09-08 | Hoffmann La Roche | inibidores macrocíclicos de jak |
WO2011161217A2 (en) | 2010-06-23 | 2011-12-29 | Palacký University in Olomouc | Targeting of vegfr2 |
PT2688887E (pt) | 2011-03-23 | 2015-07-06 | Amgen Inc | Inibidores duais tricíclicos fusionados de cdk 4/6 e flt3 |
US9745288B2 (en) | 2011-08-16 | 2017-08-29 | Indiana University Research And Technology Corporation | Compounds and methods for treating cancer by inhibiting the urokinase receptor |
RU2628074C2 (ru) * | 2011-09-30 | 2017-08-14 | Си энд Си РИСЕРЧ ЛЭБОРЕТРИЗ | ТРИЦИКЛИЧЕСКИЕ АЗОТСОДЕРЖАЩИЕ ПРОИЗВОДНЫЕ ИМИДАЗО[4,5-с]ПИРИДИНА, ОБЛАДАЮЩИЕ ИНГИБИРУЮЩЕЙ АКТИВНОСТЬЮ В ОТНОШЕНИИ РЕЦЕПТОРА ГИСТАМИНА 4 (hH4R) |
AR090263A1 (es) | 2012-03-08 | 2014-10-29 | Hoffmann La Roche | Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma |
US9505749B2 (en) | 2012-08-29 | 2016-11-29 | Amgen Inc. | Quinazolinone compounds and derivatives thereof |
JOP20190154B1 (ar) | 2016-12-22 | 2022-09-15 | Amgen Inc | بنز أيزو ثيازول، أيزو ثيازولو [3، 4-b] بيريدين، كينازولين، فثالازين، بيريدو [2، 3-d] بيريدازين ومشتقات بيريدو [2، 3-d] بيريميدين على هيئة مثبطات kras g12c لمعالجة سرطان الرئة، أو سرطان البنكرياس أو سرطان القولون والمستقيم |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
ES2928576T3 (es) | 2017-09-08 | 2022-11-21 | Amgen Inc | Inhibidores de KRAS G12C y métodos de uso de los mismos |
MA52501A (fr) | 2018-05-04 | 2021-03-10 | Amgen Inc | Inhibiteurs de kras g12c et leurs procédés d'utilisation |
MA52496A (fr) | 2018-05-04 | 2021-03-10 | Amgen Inc | Inhibiteurs de kras g12c et leurs procédés d'utilisation |
MX2020011907A (es) | 2018-05-10 | 2021-01-29 | Amgen Inc | Inhibidores de kras g12c para el tratamiento de cancer. |
CA3098885A1 (en) | 2018-06-01 | 2019-12-05 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
EP3802537A1 (de) | 2018-06-11 | 2021-04-14 | Amgen Inc. | Kras-g12c-inhibitoren zur behandlung von krebs |
JP7369719B2 (ja) | 2018-06-12 | 2023-10-26 | アムジエン・インコーポレーテツド | KRas G12C阻害剤及びそれを使用する方法 |
JP2020090482A (ja) | 2018-11-16 | 2020-06-11 | アムジエン・インコーポレーテツド | Kras g12c阻害剤化合物の重要な中間体の改良合成法 |
CA3117222A1 (en) | 2018-11-19 | 2020-05-28 | Amgen Inc. | Kras g12c inhibitors and methods of using the same |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
CA3123044A1 (en) | 2018-12-20 | 2020-06-25 | Amgen Inc. | Heteroaryl amides useful as kif18a inhibitors |
MX2021007104A (es) | 2018-12-20 | 2021-08-11 | Amgen Inc | Inhibidores de kif18a. |
MA54543A (fr) | 2018-12-20 | 2022-03-30 | Amgen Inc | Inhibiteurs de kif18a |
JP2022513967A (ja) | 2018-12-20 | 2022-02-09 | アムジエン・インコーポレーテツド | Kif18a阻害剤として有用なヘテロアリールアミド |
CN113767100A (zh) | 2019-03-01 | 2021-12-07 | 锐新医药公司 | 双环杂芳基化合物及其用途 |
WO2020180770A1 (en) | 2019-03-01 | 2020-09-10 | Revolution Medicines, Inc. | Bicyclic heterocyclyl compounds and uses thereof |
EP3738593A1 (de) | 2019-05-14 | 2020-11-18 | Amgen, Inc | Dosierung von kras-inhibitor zur behandlung von krebserkrankungen |
CN114144414A (zh) | 2019-05-21 | 2022-03-04 | 美国安进公司 | 固态形式 |
AU2020324963A1 (en) | 2019-08-02 | 2022-02-24 | Amgen Inc. | KIF18A inhibitors |
JP2022542392A (ja) | 2019-08-02 | 2022-10-03 | アムジエン・インコーポレーテツド | Kif18a阻害剤としてのピリジン誘導体 |
CN114302880A (zh) | 2019-08-02 | 2022-04-08 | 美国安进公司 | Kif18a抑制剂 |
CA3147272A1 (en) | 2019-08-02 | 2021-02-11 | Amgen Inc. | Kif18a inhibitors |
MX2022004656A (es) | 2019-10-24 | 2022-05-25 | Amgen Inc | Derivados de piridopirimidina utiles como inhibidores de kras g12c y kras g12d en el tratamiento del cancer. |
BR112022008565A2 (pt) | 2019-11-04 | 2022-08-09 | Revolution Medicines Inc | Composto, composição farmacêutica, conjugado, métodos para tratar câncer e um distúrbio relativo à proteína ras |
TW202132315A (zh) | 2019-11-04 | 2021-09-01 | 美商銳新醫藥公司 | Ras 抑制劑 |
JP2022553859A (ja) | 2019-11-04 | 2022-12-26 | レボリューション メディシンズ インコーポレイテッド | Ras阻害剤 |
CN114901662A (zh) | 2019-11-08 | 2022-08-12 | 锐新医药公司 | 双环杂芳基化合物及其用途 |
MX2022005708A (es) | 2019-11-14 | 2022-06-08 | Amgen Inc | Sintesis mejorada del compuesto inhibidor de g12c de kras. |
MX2022005726A (es) | 2019-11-14 | 2022-06-09 | Amgen Inc | Sintesis mejorada del compuesto inhibidor de g12c de kras. |
CN114980976A (zh) | 2019-11-27 | 2022-08-30 | 锐新医药公司 | 共价ras抑制剂及其用途 |
JP2023509701A (ja) | 2020-01-07 | 2023-03-09 | レヴォリューション・メディスンズ,インコーポレイテッド | Shp2阻害剤投薬およびがんを処置する方法 |
IL299131A (en) | 2020-06-18 | 2023-02-01 | Revolution Medicines Inc | Methods for delaying, preventing and treating acquired resistance to RAS inhibitors |
EP4208261A1 (de) | 2020-09-03 | 2023-07-12 | Revolution Medicines, Inc. | Verwendung von sos1-inhibitoren zur behandlung von malignitäten mit shp2-mutationen |
EP4214209A1 (de) | 2020-09-15 | 2023-07-26 | Revolution Medicines, Inc. | Indolderivate als ras-inhibitoren bei der behandlung von krebs |
AR124449A1 (es) | 2020-12-22 | 2023-03-29 | Qilu Regor Therapeutics Inc | Inhibidores de sos1 y usos de los mismos |
KR102615822B1 (ko) * | 2021-04-23 | 2023-12-19 | 재단법인 대구경북첨단의료산업진흥재단 | 이미다조[1,5-a]피리도[3,2-e]피라진 유도체 화합물 및 이를 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물 |
WO2022235866A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Covalent ras inhibitors and uses thereof |
EP4334321A1 (de) | 2021-05-05 | 2024-03-13 | Revolution Medicines, Inc. | Ras-inhibitoren |
CN117616031A (zh) | 2021-05-05 | 2024-02-27 | 锐新医药公司 | 用于治疗癌症的ras抑制剂 |
AR127308A1 (es) | 2021-10-08 | 2024-01-10 | Revolution Medicines Inc | Inhibidores ras |
WO2023114954A1 (en) | 2021-12-17 | 2023-06-22 | Genzyme Corporation | Pyrazolopyrazine compounds as shp2 inhibitors |
EP4227307A1 (de) | 2022-02-11 | 2023-08-16 | Genzyme Corporation | Pyrazolopyrazinverbindungen als shp2-inhibitoren |
WO2023172940A1 (en) | 2022-03-08 | 2023-09-14 | Revolution Medicines, Inc. | Methods for treating immune refractory lung cancer |
WO2023240263A1 (en) | 2022-06-10 | 2023-12-14 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
WO2024081916A1 (en) | 2022-10-14 | 2024-04-18 | Black Diamond Therapeutics, Inc. | Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives |
US11905290B1 (en) | 2023-09-05 | 2024-02-20 | King Faisal University | 5-substituted aminopyrimido[6′,1′:2,3]imidazo[4,5-c][1,6]naphthyridine compounds as CK2 inhibitors |
Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4160097A (en) * | 1977-01-07 | 1979-07-03 | Westwind Pharmaceuticals, Inc. | 1-(2-Phenylureylene)imidazoles |
US4172947A (en) * | 1977-01-07 | 1979-10-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
US4191766A (en) * | 1977-01-07 | 1980-03-04 | Westwood Pharmaceuticals, Inc. | Method for reducing immunological response |
US4191767A (en) * | 1977-01-07 | 1980-03-04 | Westwood Pharmaceuticals, Inc. | Method for treating fungal infection in mammals with imidazo [1,2-a]quinoxalines |
US4197403A (en) * | 1977-01-07 | 1980-04-08 | Westwood Pharmaceuticals Inc. | 4-Aminosubstituted imidazo(1,2-A)quinoxalines |
US4198508A (en) * | 1977-01-07 | 1980-04-15 | Westwood Pharmaceuticals Inc. | Process for preparing 4-substituted imidazo[1,2-a]quinoxalines |
US4200750A (en) * | 1977-01-07 | 1980-04-29 | Westwood Pharmaceuticals Inc. | 4-Substituted imidazo [1,2-a]quinoxalines |
US4225724A (en) * | 1977-01-07 | 1980-09-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Phenylureylene)imidazoles |
US4229452A (en) * | 1977-01-07 | 1980-10-21 | Westwood Pharmaceuticals, Inc. | Treatment of inflammatory disorders with 4-trifluoromethylimidazo[1,2-a]quinoxaline |
US4236015A (en) * | 1977-01-07 | 1980-11-25 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
US4317682A (en) * | 1979-08-27 | 1982-03-02 | Toyo Ink Manufacturing Co. Ltd. | Pigment compositions and use thereof |
US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
US5034530A (en) * | 1988-06-14 | 1991-07-23 | Novo Nordisk A/S | Imidazoquinoxaline compounds and their preparation and use |
US5276028A (en) * | 1990-06-22 | 1994-01-04 | Nordisk A/S | Imidazoquinoxaline compounds |
EP0728481A2 (de) * | 1995-02-27 | 1996-08-28 | Bayer Ag | Verwendun von Chinoxalinen in Kombination mit Protease-Inhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen |
WO1997019079A1 (en) * | 1995-11-24 | 1997-05-29 | Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. | IMIDAZO[1,2-a]QUINOXALIN-4-AMINES ACTIVE AS ADENOSINE ANTAGONISTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF |
WO1999010341A1 (en) * | 1997-08-25 | 1999-03-04 | Bristol-Myers Squibb Company | Imidazoquinoxaline protein tyrosine kinase inhibitors |
WO1999009845A1 (en) * | 1997-08-25 | 1999-03-04 | Bristol-Myers Squibb Company | Imidazoquinoxaline protein tyrosine kinase inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0562440B1 (de) * | 1992-03-18 | 1998-12-23 | Takeda Chemical Industries, Ltd. | Imidazopyridazine als Antiasthmatika |
-
1999
- 1999-03-01 WO PCT/US1999/004499 patent/WO1999045009A1/en active IP Right Grant
- 1999-03-01 AU AU33137/99A patent/AU756838B2/en not_active Ceased
- 1999-03-01 DE DE69940808T patent/DE69940808D1/de not_active Expired - Fee Related
- 1999-03-01 CA CA002322311A patent/CA2322311C/en not_active Expired - Fee Related
- 1999-03-01 ES ES99937929T patent/ES2324846T3/es not_active Expired - Lifetime
- 1999-03-01 JP JP2000534551A patent/JP2002505330A/ja active Pending
- 1999-03-01 EP EP99937929A patent/EP1066286B1/de not_active Expired - Lifetime
- 1999-03-01 AT AT99937929T patent/ATE430149T1/de not_active IP Right Cessation
- 1999-03-03 ZA ZA9901721A patent/ZA991721B/xx unknown
- 1999-03-04 AR ARP990100925A patent/AR018311A1/es unknown
- 1999-03-04 US US09/262,525 patent/US5990109A/en not_active Expired - Lifetime
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4160097A (en) * | 1977-01-07 | 1979-07-03 | Westwind Pharmaceuticals, Inc. | 1-(2-Phenylureylene)imidazoles |
US4172947A (en) * | 1977-01-07 | 1979-10-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
US4191766A (en) * | 1977-01-07 | 1980-03-04 | Westwood Pharmaceuticals, Inc. | Method for reducing immunological response |
US4191767A (en) * | 1977-01-07 | 1980-03-04 | Westwood Pharmaceuticals, Inc. | Method for treating fungal infection in mammals with imidazo [1,2-a]quinoxalines |
US4197403A (en) * | 1977-01-07 | 1980-04-08 | Westwood Pharmaceuticals Inc. | 4-Aminosubstituted imidazo(1,2-A)quinoxalines |
US4198508A (en) * | 1977-01-07 | 1980-04-15 | Westwood Pharmaceuticals Inc. | Process for preparing 4-substituted imidazo[1,2-a]quinoxalines |
US4200750A (en) * | 1977-01-07 | 1980-04-29 | Westwood Pharmaceuticals Inc. | 4-Substituted imidazo [1,2-a]quinoxalines |
US4225724A (en) * | 1977-01-07 | 1980-09-30 | Westwood Pharmaceuticals, Inc. | 1-(2-Phenylureylene)imidazoles |
US4229452A (en) * | 1977-01-07 | 1980-10-21 | Westwood Pharmaceuticals, Inc. | Treatment of inflammatory disorders with 4-trifluoromethylimidazo[1,2-a]quinoxaline |
US4236015A (en) * | 1977-01-07 | 1980-11-25 | Westwood Pharmaceuticals, Inc. | 1-(2-Acylaminophenyl)imidazoles |
US4317682A (en) * | 1979-08-27 | 1982-03-02 | Toyo Ink Manufacturing Co. Ltd. | Pigment compositions and use thereof |
US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
US5034530A (en) * | 1988-06-14 | 1991-07-23 | Novo Nordisk A/S | Imidazoquinoxaline compounds and their preparation and use |
US5276028A (en) * | 1990-06-22 | 1994-01-04 | Nordisk A/S | Imidazoquinoxaline compounds |
EP0728481A2 (de) * | 1995-02-27 | 1996-08-28 | Bayer Ag | Verwendun von Chinoxalinen in Kombination mit Protease-Inhibitoren als Arzneimittel zur Behandlung von AIDS und/oder HIV-Infektionen |
WO1997019079A1 (en) * | 1995-11-24 | 1997-05-29 | Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. | IMIDAZO[1,2-a]QUINOXALIN-4-AMINES ACTIVE AS ADENOSINE ANTAGONISTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF |
WO1999010341A1 (en) * | 1997-08-25 | 1999-03-04 | Bristol-Myers Squibb Company | Imidazoquinoxaline protein tyrosine kinase inhibitors |
WO1999009845A1 (en) * | 1997-08-25 | 1999-03-04 | Bristol-Myers Squibb Company | Imidazoquinoxaline protein tyrosine kinase inhibitors |
Non-Patent Citations (20)
Title |
---|
Bolen,J. B., et al., FASEB Journal , The Src family of tyrosine protein kinases in hemopoietic signal transduction , vol. 6, pp. 3403 3409 (1992). * |
Bolen,J. B., et al., FASEB Journal, "The Src family of tyrosine protein kinases in hemopoietic signal transduction", vol. 6, pp. 3403-3409 (1992). |
Chan, A.C., et al., EMBO Journal , Activation of ZAP 70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function , vol. 14, pp. 2499 2508, (1995). * |
Chan, A.C., et al., EMBO Journal, "Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function", vol. 14, pp. 2499-2508, (1995). |
Cooper, J. A., et al., Journal of Biological Chemistry , Phosphorylation Sites in Enolase and Lactate Dehydrogenase Utilized by Tyrosine Protein Kinases in Vivo and In Vitro , vol. 259, No. 12, pp. 7835 7841 (1984). * |
Cooper, J. A., et al., Journal of Biological Chemistry, "Phosphorylation Sites in Enolase and Lactate Dehydrogenase Utilized by Tyrosine Protein Kinases in Vivo and In Vitro", vol. 259, No. 12, pp. 7835-7841 (1984). |
Davey, D.D., et al. J.Med. Chem. "Novel Compounds Possessing Potent cAMP and cGMP Phosphodiesterase Inhibitory Activity. Synthesis and Cardiovascular Effects of a Series of Imidazo[1,2-a]quinnoxalinones and Imidazo[1,5-a]quinoxalinones and Their AZA Analogues" vol. 34, pp. 2671-2677 (1991). |
Davey, D.D., et al. J.Med. Chem. Novel Compounds Possessing Potent cAMP and cGMP Phosphodiesterase Inhibitory Activity. Synthesis and Cardiovascular Effects of a Series of Imidazo 1,2 a quinnoxalinones and Imidazo 1,5 a quinoxalinones and Their AZA Analogues vol. 34, pp. 2671 2677 (1991). * |
Ihle, J. N., Seminars in Immunology , The Janus protein tyrosine kinases in hematopoietic cytokine , vol.7, pp. 247 254 (1995). * |
Ihle, J. N., Seminars in Immunology, "The Janus protein tyrosine kinases in hematopoietic cytokine", vol.7, pp. 247-254 (1995). |
Iwashima, M., et al., Science , Sequential Interactions of the TCR with Two Distinct Cytoplasmic Tyrosine Kinases , vol. 263, pp. 1136 1139 (1994). * |
Iwashima, M., et al., Science, "Sequential Interactions of the TCR with Two Distinct Cytoplasmic Tyrosine Kinases", vol. 263, pp. 1136-1139 (1994). |
Schieven, G. L., et al., Journal of Biological Chemistry, "ZAP-70 Tyrosine Kinase, CD45, and T Cell Receptor Involvement in UV-and H2 O2 -induced T Cell Signal Transduction", vol. 269, No. 32, pp. 20718-20726 (1994). |
Schieven, G. L., et al., Journal of Biological Chemistry, ZAP 70 Tyrosine Kinase, CD45, and T Cell Receptor Involvement in UV and H 2 O 2 induced T Cell Signal Transduction , vol. 269, No. 32, pp. 20718 20726 (1994). * |
U.S. Application Serial No. 09/094,797; Imidazoquinoxaline Protein Tyrosine Kinase Inhibitors; Filed Jun. 15, 1998. * |
U.S. Application Serial No. 09/097,338; Imidazoquinoxaline Protein Tyrosine Kinase Inhibitors; Filed Jun. 15, 1998. * |
Ulrich, A., et al., Cell , Signal Transduction by Receptors with Tyrosine Kinase Activity , vol. 61, pp. 203 212 (1990). * |
Ulrich, A., et al., Cell, "Signal Transduction by Receptors with Tyrosine Kinase Activity", vol. 61, pp. 203-212 (1990). |
Weiss, A., et al., Cell , Signal Transduction by Lymphocyte Antigen Receptors , vol. 76, pp. 263 274 (1994). * |
Weiss, A., et al., Cell, "Signal Transduction by Lymphocyte Antigen Receptors", vol. 76, pp. 263-274 (1994). |
Cited By (158)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070014832A1 (en) * | 1999-12-07 | 2007-01-18 | Rutgers, The State Univesity Of New Jersey | Therapeutic compositions and methods |
US8088405B2 (en) * | 1999-12-07 | 2012-01-03 | Rutgers, The State University of New Jersery | Therapeutic compositions and methods |
US20010055593A1 (en) * | 2000-03-14 | 2001-12-27 | Joseph Sypek | Use of rapamycin and agents that inhibit B7 activity in immunomodulation |
US20070092506A1 (en) * | 2000-03-14 | 2007-04-26 | Genetics Institute, Llc | Use of rapamycin and agents that inhibit B7 activity in immunomodulation |
US6960585B2 (en) | 2000-10-03 | 2005-11-01 | Bristol-Myers Squibb Company | Amino-substituted tetracyclic compounds useful as anti-inflammatory agents and pharmaceutical compositions comprising same |
WO2002047710A2 (en) * | 2000-12-11 | 2002-06-20 | Children's Medical Center Corporation | Use of inhibitors of lyn-associated signal transduction (last) in the treatment of prostate cancer |
US20020151497A1 (en) * | 2000-12-11 | 2002-10-17 | Children's Medical Center Corporation | Treatment of prostate cancer by inhibiting Lyn tyrosine kinase |
WO2002047710A3 (en) * | 2000-12-11 | 2003-04-24 | Childrens Medical Center | Use of inhibitors of lyn-associated signal transduction (last) in the treatment of prostate cancer |
US20040110177A1 (en) * | 2001-02-02 | 2004-06-10 | Axel Ullrich | Method for identifying functional nucleic acids |
WO2002063037A2 (en) * | 2001-02-02 | 2002-08-15 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Method for identifying functional nucleic acids |
WO2002063037A3 (en) * | 2001-02-02 | 2003-10-02 | Max Planck Gesellschaft | Method for identifying functional nucleic acids |
US9456970B2 (en) | 2001-05-31 | 2016-10-04 | Upsher-Smith Laboratories, Inc. | Dermatological compositions and methods |
US8013017B2 (en) | 2001-05-31 | 2011-09-06 | Upsher-Smith Laboratories, Inc. | Dermatological compositions and methods |
US20100280036A1 (en) * | 2002-03-08 | 2010-11-04 | Aldo Ammendola | Modulation of Pathogenicity |
US20080188536A1 (en) * | 2002-03-08 | 2008-08-07 | Aldo Ammendola | Modulation of pathogenicity |
US20040235914A1 (en) * | 2002-03-08 | 2004-11-25 | 4 Sc Ag | Modulation of pathogenicity |
US20040063765A1 (en) * | 2002-03-08 | 2004-04-01 | 4 Sc Ag | Modulation of pathogenicity |
US7335779B2 (en) | 2002-03-08 | 2008-02-26 | Quonova, Llc | Modulation of pathogenicity |
US7338969B2 (en) | 2002-03-08 | 2008-03-04 | Quonova, Llc | Modulation of pathogenicity |
US20080176938A1 (en) * | 2002-03-08 | 2008-07-24 | Aldo Ammendola | Modulation of pathogenicity |
US20080182878A1 (en) * | 2002-03-08 | 2008-07-31 | Aldo Ammendola | Modulation of pathogenicity |
US20080188491A1 (en) * | 2002-03-08 | 2008-08-07 | Aldo Ammendola | Modulation of pathogenicity |
US20080188535A1 (en) * | 2002-03-08 | 2008-08-07 | Aldo Ammendola | Modulation of pathogenicity |
US20080194588A1 (en) * | 2002-03-08 | 2008-08-14 | Aldo Ammendola | Modulation of pathogcnicity |
US20100280034A1 (en) * | 2002-03-08 | 2010-11-04 | Aldo Ammendola | Modulation of pathogenicity |
US20090076012A1 (en) * | 2002-03-08 | 2009-03-19 | Aldo Ammendola | Modulation of pathogenicity |
US20080214635A1 (en) * | 2002-03-08 | 2008-09-04 | Aldo Ammendola | Modulation of pathogenicity |
US20080194607A1 (en) * | 2002-03-08 | 2008-08-14 | Aldo Ammendola | Modulation of pathogenicity |
WO2003097044A1 (en) * | 2002-05-16 | 2003-11-27 | Pharmacia Corporation | Methods using a combination of a 3-heteroaryl-2-indolinone and a cyclooxygenase-2 inhibitor for the treatment of neoplasia |
WO2004004644A3 (en) * | 2002-07-05 | 2004-05-06 | Beth Israel Hospital | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
WO2004004644A2 (en) * | 2002-07-05 | 2004-01-15 | Beth Israel Deaconess Medical Center | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
US20060094674A1 (en) * | 2002-07-05 | 2006-05-04 | Neel Benjamin G | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
US20110130429A1 (en) * | 2002-12-06 | 2011-06-02 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US20040171587A1 (en) * | 2002-12-06 | 2004-09-02 | Borgens Richard B. | Pyridines for treating injured mammalian nerve tissue |
US7244748B2 (en) * | 2002-12-06 | 2007-07-17 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US8097638B2 (en) | 2002-12-06 | 2012-01-17 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US20080039490A1 (en) * | 2002-12-06 | 2008-02-14 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US8729107B2 (en) | 2002-12-06 | 2014-05-20 | Purdue Research Foundation | Pyridines for treating injured mammalian nerve tissue |
US20040180898A1 (en) * | 2003-03-03 | 2004-09-16 | Bang-Chi Chen | Processes for preparing imidazoquinoxalinones, heterocyclic-substituted imidazopyrazinones, imidazoquinoxalines and heterocyclic-substituted imidazopyrazines |
US20050008640A1 (en) * | 2003-04-23 | 2005-01-13 | Wendy Waegell | Method of treating transplant rejection |
US20070208012A1 (en) * | 2003-05-06 | 2007-09-06 | Aldo Ammendola | Modulation of Pathogenicity |
US20070093534A1 (en) * | 2003-05-06 | 2007-04-26 | Aldo Ammendola | Modulation of Pathogenicity |
US20070196340A1 (en) * | 2003-05-06 | 2007-08-23 | Aldo Ammendola | Modulation of Pathogenicity |
US20070197492A1 (en) * | 2003-05-06 | 2007-08-23 | Aldo Ammendola | Modulation of Pathogenicity |
US20070184014A1 (en) * | 2003-05-06 | 2007-08-09 | Aldo Ammendola | Modulation of Pathogenicity |
US20050131018A1 (en) * | 2003-08-20 | 2005-06-16 | Axys Pharmaceuticals, Inc. | Acetylene derivatives as inhibitors of histone deacetylase |
US7368572B2 (en) | 2003-08-20 | 2008-05-06 | Pharmacyclics, Inc. | Acetylene derivatives as inhibitors of histone deacetylase |
US20080139547A1 (en) * | 2003-08-20 | 2008-06-12 | Pharmacyclics, Inc. | Acetylene derivatives as inhibitors of histone deacetylase |
US20060079556A1 (en) * | 2004-10-12 | 2006-04-13 | Sher Philip M | N-sulfonylpiperidine cannabinoid receptor 1 antagonists |
US7517991B2 (en) | 2004-10-12 | 2009-04-14 | Bristol-Myers Squibb Company | N-sulfonylpiperidine cannabinoid receptor 1 antagonists |
US20060155126A1 (en) * | 2005-01-12 | 2006-07-13 | Chongqing Sun | Bicyclic heterocycles as cannabinoid receptor modulators |
US20060154955A1 (en) * | 2005-01-12 | 2006-07-13 | Chongqing Sun | Bicyclic heterocycles as cannabinoid receptor modulators |
US7314882B2 (en) | 2005-01-12 | 2008-01-01 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
US7361766B2 (en) | 2005-01-12 | 2008-04-22 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
US7220859B2 (en) | 2005-01-12 | 2007-05-22 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
US7368458B2 (en) | 2005-01-12 | 2008-05-06 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid receptor modulators |
US7709647B2 (en) | 2005-01-18 | 2010-05-04 | Bristol-Myers Squibb Company | Tetrahydroquinoline cannabinoid receptor modulators |
US20080200459A1 (en) * | 2005-01-18 | 2008-08-21 | Bristol-Myers Squibb Company | Tetrahydroquinoline cannabinoid receptor modulators |
US7238702B2 (en) | 2005-02-10 | 2007-07-03 | Bristol-Myers Squibb Company | Dihydroquinazolinones as 5HT modulators |
US20060178386A1 (en) * | 2005-02-10 | 2006-08-10 | Saleem Ahmad | Dihydroquinazolinones as 5HT modulators |
US7452892B2 (en) | 2005-06-17 | 2008-11-18 | Bristol-Myers Squibb Company | Triazolopyrimidine cannabinoid receptor 1 antagonists |
US7632837B2 (en) | 2005-06-17 | 2009-12-15 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
US20060287324A1 (en) * | 2005-06-17 | 2006-12-21 | Chongqing Sun | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
US20100048612A1 (en) * | 2005-06-17 | 2010-02-25 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
US7629342B2 (en) | 2005-06-17 | 2009-12-08 | Bristol-Myers Squibb Company | Azabicyclic heterocycles as cannabinoid receptor modulators |
US7572808B2 (en) | 2005-06-17 | 2009-08-11 | Bristol-Myers Squibb Company | Triazolopyridine cannabinoid receptor 1 antagonists |
US20060287341A1 (en) * | 2005-06-17 | 2006-12-21 | Gang Wu | Triazolopyrimidine cannabinoid receptor 1 antagonists |
US20060287323A1 (en) * | 2005-06-17 | 2006-12-21 | Ewing William R | Azabicyclic heterocycles as cannabinoid receptor modulators |
US20070004772A1 (en) * | 2005-06-17 | 2007-01-04 | Chongqing Sun | Triazolopyridine cannabinoid receptor 1 antagonists |
US7858639B2 (en) | 2005-06-17 | 2010-12-28 | Bristol-Myers Squibb Company | Bicyclic heterocycles as cannabinoid-1 receptor modulators |
US20060287342A1 (en) * | 2005-06-17 | 2006-12-21 | Mikkilineni Amarendra B | Triazolopyrimidine heterocycles as cannabinoid receptor modulators |
US20070027178A1 (en) * | 2005-07-28 | 2007-02-01 | Bristol-Myers Squibb Company | Substituted tetrahydro-1H-pyrido[4,3-b]indoles as serotonin receptors agonists and antagonists |
US20070049613A1 (en) * | 2005-08-24 | 2007-03-01 | Bristol-Myers Squibb Company | Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists |
US7795436B2 (en) | 2005-08-24 | 2010-09-14 | Bristol-Myers Squibb Company | Substituted tricyclic heterocycles as serotonin receptor agonists and antagonists |
US8557818B2 (en) | 2006-12-14 | 2013-10-15 | Vertex Phamaceuticals Incorporated | Compounds useful as protein kinase inhibitors |
US20100179158A1 (en) * | 2007-04-20 | 2010-07-15 | Hoffman Charles S | Inhibitors of cyclic amp phosphodiesterases |
EP2226322B1 (de) * | 2007-12-27 | 2015-01-21 | Daiichi Sankyo Company, Limited | Imidazol-carbonyl-verbindung |
EP2226322A1 (de) * | 2007-12-27 | 2010-09-08 | Daiichi Sankyo Company, Limited | Imidazol-carbonyl-verbindung |
US9822131B2 (en) | 2008-01-04 | 2017-11-21 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9216982B2 (en) | 2008-01-04 | 2015-12-22 | Intellikine Llc | Certain chemical entities, compositions and methods |
US9655892B2 (en) | 2008-01-04 | 2017-05-23 | Intellikine Llc | Certain chemical entities, compositions and methods |
US11433065B2 (en) | 2008-01-04 | 2022-09-06 | Intellikine Llc | Certain chemical entities, compositions and methods |
US20100227853A1 (en) * | 2008-04-18 | 2010-09-09 | Trustees Of Boston College | Inhibitors of cyclic amp phosphodiesterases |
US9365579B2 (en) | 2008-06-10 | 2016-06-14 | Abbvie Inc. | Tricyclic compounds |
US8962629B2 (en) | 2008-06-10 | 2015-02-24 | Abbvie Inc. | Tricyclic compounds |
US20090312338A1 (en) * | 2008-06-10 | 2009-12-17 | Abbott Laboratories | Novel Tricyclic Compounds |
US8618106B2 (en) | 2008-06-23 | 2013-12-31 | Vertex Pharmaceuticals Incorporated | Protein kinase inhibitors |
US20100135908A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Delivery devices for modulating inflammation |
US20100136094A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100137246A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136096A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100135983A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100137247A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Anti-inflammatory compositions and methods |
US20100136097A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US20100136095A1 (en) * | 2008-12-02 | 2010-06-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Systems for modulating inflammation |
US9206182B2 (en) | 2009-07-15 | 2015-12-08 | Intellikine Llc | Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof |
US9522146B2 (en) | 2009-07-15 | 2016-12-20 | Intellikine Llc | Substituted Isoquinolin-1(2H)-one compounds, compositions, and methods thereof |
US20110059961A1 (en) * | 2009-09-08 | 2011-03-10 | Xiaojing Wang | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
US8435976B2 (en) | 2009-09-08 | 2013-05-07 | F. Hoffmann-La Roche | 4-substituted pyridin-3-yl-carboxamide compounds and methods of use |
US20110190489A1 (en) * | 2009-12-01 | 2011-08-04 | Abbott Laboratories | Novel Tricyclic Compounds |
USRE47221E1 (en) | 2009-12-01 | 2019-02-05 | Abbvie Inc. | Tricyclic compounds |
US8785639B2 (en) | 2009-12-01 | 2014-07-22 | Abbvie Inc. | Substituted dihydropyrazolo[3,4-D]pyrrolo[2,3-B]pyridines and methods of use thereof |
CN102711470A (zh) * | 2009-12-01 | 2012-10-03 | 雅培制药有限公司 | 新的三环化合物 |
US20110171218A1 (en) * | 2009-12-02 | 2011-07-14 | Acceleron Pharma Inc. | Compositions and methods for increasing serum half-life |
US8722615B2 (en) | 2009-12-02 | 2014-05-13 | Acceleron Pharma, Inc. | Compositions and methods for increasing serum half-life |
US11312718B2 (en) | 2011-01-10 | 2022-04-26 | Infinity Pharmaceuticals, Inc. | Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one |
US10550122B2 (en) | 2011-01-10 | 2020-02-04 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof |
US9290497B2 (en) | 2011-01-10 | 2016-03-22 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
USRE46621E1 (en) | 2011-01-10 | 2017-12-05 | Infinity Pharmaceuticals, Inc. | Processes for preparing isoquinolinones and solid forms of isoquinolinones |
US9840505B2 (en) | 2011-01-10 | 2017-12-12 | Infinity Pharmaceuticals, Inc. | Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof |
US8883982B2 (en) | 2011-06-08 | 2014-11-11 | Acceleron Pharma, Inc. | Compositions and methods for increasing serum half-life |
US9365575B2 (en) | 2012-05-21 | 2016-06-14 | Allergan, Inc. | Kinase inhibitors |
US9527847B2 (en) | 2012-06-25 | 2016-12-27 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
US8828998B2 (en) * | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
US20130344061A1 (en) * | 2012-06-25 | 2013-12-26 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors |
US9387250B2 (en) | 2013-03-15 | 2016-07-12 | Rutgers, The State University Of New Jersey | Therapeutic compositions for bone repair |
US11944631B2 (en) | 2014-04-16 | 2024-04-02 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11110096B2 (en) | 2014-04-16 | 2021-09-07 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US10519164B2 (en) | 2015-10-16 | 2019-12-31 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3,ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11718627B2 (en) | 2015-10-16 | 2023-08-08 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11976077B2 (en) | 2015-10-16 | 2024-05-07 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms therof |
US10344036B2 (en) | 2015-10-16 | 2019-07-09 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-#a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-#carboxamide and solid state forms thereof |
US10202393B2 (en) | 2015-10-16 | 2019-02-12 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9879019B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10017517B2 (en) | 2015-10-16 | 2018-07-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluorethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10550126B2 (en) | 2015-10-16 | 2020-02-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10597400B2 (en) | 2015-10-16 | 2020-03-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof |
US10730883B2 (en) | 2015-10-16 | 2020-08-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11795175B2 (en) | 2015-10-16 | 2023-10-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10981924B2 (en) | 2015-10-16 | 2021-04-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10981923B2 (en) | 2015-10-16 | 2021-04-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[l,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10995095B2 (en) | 2015-10-16 | 2021-05-04 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof |
US9963459B1 (en) | 2015-10-16 | 2018-05-08 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-alpla]pyrrolo[2,3-e]-pyrazin-8-YL)-N-(2,2,2-Trifluoroethyl)pyrrol and solid state forms thereof |
US11787815B1 (en) | 2015-10-16 | 2023-10-17 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11186584B2 (en) | 2015-10-16 | 2021-11-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11198697B1 (en) | 2015-10-16 | 2021-12-14 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9951080B2 (en) | 2015-10-16 | 2018-04-24 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-alpha]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11365198B2 (en) | 2015-10-16 | 2022-06-21 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US9879018B2 (en) | 2015-10-16 | 2018-01-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl and solid state forms thereof |
US11512092B2 (en) | 2015-10-16 | 2022-11-29 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11524964B2 (en) | 2015-10-16 | 2022-12-13 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11535626B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1 carboxamide and solid state forms thereof |
US11535625B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11535624B2 (en) | 2015-10-16 | 2022-12-27 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-α]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11661425B2 (en) | 2015-10-16 | 2023-05-30 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11680069B2 (en) | 2015-10-16 | 2023-06-20 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US10202394B2 (en) | 2015-10-16 | 2019-02-12 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11767326B2 (en) | 2015-10-16 | 2023-09-26 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11773105B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]- pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11773106B2 (en) | 2015-10-16 | 2023-10-03 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11780847B1 (en) | 2015-10-16 | 2023-10-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof |
US11780848B2 (en) | 2015-10-16 | 2023-10-10 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1- carboxamide and solid state forms thereof |
US10807968B2 (en) | 2016-02-11 | 2020-10-20 | Bayer Cropscience Aktiengesellschaft | Substituted 2-(het)arylimidazolylcarboxyamides as pesticides |
US10544124B2 (en) * | 2016-02-11 | 2020-01-28 | Bayer Cropscience Aktiengesellschaft | Substituted 2-(het)arylimidazolylcarboxyamides as pesticides |
US20190047982A1 (en) * | 2016-02-11 | 2019-02-14 | Bayer Cropscience Aktiengesellschaft | Substituted 2-(het)arylimidazolylcarboxyamides as pesticides |
US11147818B2 (en) | 2016-06-24 | 2021-10-19 | Infinity Pharmaceuticals, Inc. | Combination therapies |
US11993605B2 (en) | 2023-03-01 | 2024-05-28 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
US11993606B2 (en) | 2023-08-21 | 2024-05-28 | Abbvie Inc. | Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and solid state forms thereof |
Also Published As
Publication number | Publication date |
---|---|
AR018311A1 (es) | 2001-11-14 |
DE69940808D1 (de) | 2009-06-10 |
AU756838B2 (en) | 2003-01-23 |
JP2002505330A (ja) | 2002-02-19 |
ZA991721B (en) | 2000-10-10 |
EP1066286B1 (de) | 2009-04-29 |
ATE430149T1 (de) | 2009-05-15 |
CA2322311C (en) | 2009-10-13 |
AU3313799A (en) | 1999-09-20 |
EP1066286A4 (de) | 2004-02-11 |
EP1066286A1 (de) | 2001-01-10 |
WO1999045009A1 (en) | 1999-09-10 |
CA2322311A1 (en) | 1999-09-10 |
ES2324846T3 (es) | 2009-08-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5990109A (en) | Heterocyclo-substituted imidazopyrazine protein tyrosine kinase inhibitors | |
US6635626B1 (en) | Imidazoquinoxaline protein tyrosine kinase inhibitors | |
ES2274986T3 (es) | Derivados de benzimidazo 4,5-f/isoquinolinona. | |
US6235740B1 (en) | Imidazoquinoxaline protein tyrosine kinase inhibitors | |
US7371750B2 (en) | Compounds and compositions as protein kinase inhibitors | |
US8518953B2 (en) | Aminopyrimidines useful as inhibitors of protein kinases | |
AU2002355732A1 (en) | Benzimidazo[4,5-f]isoquinolinone derivatives | |
JP2000128883A (ja) | 性的機能障害の治療用のピラゾロピリミジノンcGMPPDE5阻害剤 | |
CA2619365A1 (en) | Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators | |
CA2977659A1 (en) | Salts of pi3k inhibitor and processes for their preparation | |
KR20050115277A (ko) | 단백질 키나아제 저해제 | |
EA027752B1 (ru) | Терапевтически активные производные пиразолопиримидина | |
CA2922044A1 (en) | Pyrazolo-, imidazolo- and pyrrolo-pyridine or -pyrimidine derivatives as inhibitors o brutons kinase (btk) | |
CA3181209A1 (en) | Inhibitors of fibroblast growth factor receptor kinases | |
US6630476B2 (en) | Pyrrolo [3,4-d] pyrimidines as corticotropin releasing factor (CRF) antagonists | |
CN111499613B (zh) | N-甲酰胺衍生物、其制备方法及其在医药上的用途 | |
US10399979B2 (en) | Janus kinase inhibitors and uses thereof | |
US6358946B1 (en) | C-6 ring-substituted pyrido[1,2-a]benzimidazole derivatives useful in treating central nervous system disorders | |
CN112778275A (zh) | 金刚烷基prmt5抑制剂及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BRISTOL-MYERS SQUIBB COMPANY, NEW JERSEY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CHEN, PING;BARRISH, JOEL C.;GU, HENRY C.;AND OTHERS;REEL/FRAME:009809/0462;SIGNING DATES FROM 19990225 TO 19990304 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
CC | Certificate of correction | ||
FPAY | Fee payment |
Year of fee payment: 8 |
|
FPAY | Fee payment |
Year of fee payment: 12 |